Franzese was born in Bensonhurst, New York, the son of Denise, a lunch lady, and Ralph "R. J." Franzese, a lounge singer. Franzese attended Piper High School in Sunrise, Florida from 1992 to 1996. His mother was a lunch lady at the school.
On April 22, 2014, Franzese came out publicly as gay, in a letter to his character in Mean Girls, to commemorate the tenth anniversary of the film. In July 2016, he got engaged to his partner Joseph Bradley Phillips.
After publicly revealing he's gay in 2014, Franzese became more active in the fight for civil and human rights in the LGBTQ community; and through his portrayal of HIV Positive character Eddie in the HBO series Looking, he has become a well known AIDS activist in the United States. In 2015 he became an ambassador for the Elizabeth Taylor AIDS Foundation.
Franzese has appeared in more than fourteen films, including Bully, Party Monster, Mean Girls, Bristol Boys and War of the Worlds.
Starting in 2011, Franzese was also featured in the web series Foodies. He portrayed Eddie in the 2015 second season of the HBO series Looking, and reprised the role for the 2016 finale special, Looking: The Movie. Franzese also starred as Vern Testaverde in the 2016 Freeform series Recovery Road. In July 2016, Franzese was cast as series regular Jackson Morrison in the ABC legal drama series Conviction.